Nephrotoxicity Associated with Cytoreductive Surgery Combined with Cisplatin-Based Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignant Disease: A Systematic Review and Meta-Analysis

Background: Cisplatin is employed in hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) for peritoneal surface malignancies (PSMs). The main concern regarding intraperitoneal cisplatin administration is nephrotoxicity. Numerous reports in this context are available. Our objective was to conduct a systematic review and meta-analysis to assess cisplatin-based HIPEC-related nephrotoxicity (CHRN). Methods: A systematic literature review on CHRN after CRS for the treatment of PSMs was performed. The literature search was carried out using Medline, Cochrane, and Embase. The last day of the search was 23 October 2023. PRISMA guidelines were used. A meta-analysis was then conducted. The main endpoint was the incidence of acute and chronic renal impairment after CHRN. Secondary endpoints included the potential impact of several clinical variables on the primary endpoint and a critical appraisal of the different renal impairment scales employed. Results: Our study included 26 articles with a total sample of 1473 patients. The incidence of acute kidney injury (AKI) was 18.6% (95% CI: 13.6–25%, range of true effects 3–59%). For chronic kidney disease, it was 7% (95% CI: 3–15.3%, range of true effects 1–53%). The variables that statistically influenced these results were the scale used to measure renal insufficiency, the use of nephroprotective agents, and the presence of pre-existing renal disease. Conclusions: The reported incidence of renal impairment following cisplatin-based HIPEC is highly variable. The incidence of renal failure obtained in this meta-analysis should be used as a reference for subsequent reports on this topic. Further prospective studies are warranted to establish optimal and standardized management.


Introduction
Peritoneal surface malignancies (PSMs) are one of the most significant clinical challenges in modern oncology.Ovarian cancer ranks as the third most prevalent gynecological [1] malignancy in women, with approximately 75% of cases being diagnosed at advanced stages (IIIB-IV), which feature peritoneal metastases (PMs) [2].In gastric cancer patients [3], PMs are present in 5-20% of cases eligible for potentially curative resection.PMs from colorectal origin are common, affecting 10-30% [4] of patients overall and approximately 7-8% at the time of primary surgery.

Outcome Measures
The primary endpoint of this systematic review and meta-analysis is the incidence of renal impairment, including both acute and chronic disfunction.To assess secondary outcomes, i.e., various clinical variables that may influence the incidence of renal impairment following HIPEC, several subgroup analyses were conducted.The following clusters were investigated: nephroprotective strategies, chemotherapeutic agents employed for HIPEC, dosage of cisplatin administered, renal impairment grading scale employed, etiology of PSM, pre-existing renal conditions, gender and age distribution, as well as study design.
Some of the included studies directly compare, in two arms, the use or non-use of pharmacological nephroprotection strategies.In order to evaluate whether this intervention influences the incidence of renal impairment, a specific interventional comparison metaanalysis was conducted in addition to the overall study.

Statistical Analysis
After data extraction, a comprehensive study of the incidence of acute renal failure following CRS and cisplatin-based HIPEC was conducted, followed by a subgroup analysis, as described earlier.A one-arm statistical analysis was conducted using Comprehensive Meta-Analysis Version 4 software [20].Revman 5 [21] was utilized for two-arm metaanalysis to evaluate the relative risk of AKI with or without nephroprotection.
The random-effects model was employed for the analysis [22], under the assumption that the studies included represent a random sample from a broader universe of potential studies, and that the results will be extrapolated to that universe.Significance was established at a 95% confidence interval (CI), with p < 0.05 considered statistically significant.Heterogeneity analysis was performed using the I-squared (I 2 ) statistic, which provides a percentage indicating the proportion of variance in the observed effects attributable to true effects rather than sampling errors.The overall analysis also includes the predictive interval, in which the incidence of all the 95% comparable population falls assuming that true effects are normally distributed.

Methodological Quality of the Included Studies and Risk of Bias Assessment
Following the Cochrane recommendations, the Joanna Briggs Institute (JBI) Critical Appraisal tool for use in systematic reviews of randomized [23] and non-randomized clinical trials [24], case series [25], cohort studies, and case-control studies [26] was used for methodological quality (risk of bias) study assessment.Each study was assessed twice based on the risk classification criteria.Studies with positive answers ≤49% were considered to have a high risk of bias; studies with scores between 50-69% were classified with a moderate risk of bias; and those with scores above 70% were categorized as studies with a low risk of bias.

Results
A total of 572 records were found.After deleting duplicates, 472 records remained for assessment.First screening by title and abstract excluded 352 records, leaving 120 articles for full-text assessment.Finally, 27 studies were included for qualitive synthesis and 26 for quantitative synthesis.The reason why one article [27] was excluded for quantitative synthesis is that the data reported were aggregated and therefore could not be discretely analyzed.
The reasons for the exclusion of 93 studies during the full-text assessment for eligibility along with the overall study selection process are shown in the PRISMA diagram (Figure 1), for more detail see Supplementary Material [7,10,.
J. Clin.Med.2024, 13, x FOR PEER REVIEW The reasons for the exclusion of 93 studies during the full-text assessment for bility along with the overall study selection process are shown in the PRISMA dia (Figure 1), for more detail see Supplementary Material [7,10,.

Characteristics of Included Studies
There were eleven cohort studies, one cases series, two case-control studies, fiv randomized clinical trials, and one randomized clinical trial (Table 2) Regardin chemotherapeutic regimens utilized during HIPEC, four studies employed a combin of cisplatin and doxorubicin, twenty used cisplatin alone, and two studies used b different arms (Liesenfeld et al. [117] and Somashekhar et al. [118]).Regarding ne protective strategies, four studies employed sodium thiosulfate and two used amifo In four studies (Lim et al. [119]; Laplace et al. [6].; Senguttuvan et al. [120]; and Gl et al. [121]), the incidence of renal failure following the intervention is directly com in two separate arms.Various criteria for renal impairment assessment were utilize FLE was employed in six instances, WHO and AKIN were each used once, CTCAE times, Clavien-Dindo in three studies, and KDIGO four times.

Characteristics of Included Studies
There were eleven cohort studies, one cases series, two case-control studies, five nonrandomized clinical trials, and one randomized clinical trial (Table 2) Regarding the chemotherapeutic regimens utilized during HIPEC, four studies employed a combination of cisplatin and doxorubicin, twenty used cisplatin alone, and two studies used both in different arms (Liesenfeld et al. [117] and Somashekhar et al. [118]).Regarding nephroprotective strategies, four studies employed sodium thiosulfate and two used amifostine.In four studies (Lim et al. [119]; Laplace et al. [6].; Senguttuvan et al. [120]; and Glennon et al. [121]), the incidence of renal failure following the intervention is directly compared in two separate arms.Various criteria for renal impairment assessment were utilized: RIFLE was employed in six instances, WHO and AKIN were each used once, CTCAE nine times, Clavien-Dindo in three studies, and KDIGO four times.

Assessment of Risk of Bias
The overall risk of bias in the analyzed studies was low, showing a high percentage of positive answers to the JBI Critical Appraisal Tools assessment (Table 3A-D).Three nonrandomized clinical trials had a moderate risk of bias (Table 3E).In these studies, negative evaluations were associated with the lack of a control group.Likewise, unclear responses in studies with moderate bias were linked to the lack of information regarding appropriate group comparisons.[25].(D) Risk of bias assessed by the JBI Critical Appraisal Tools for use in randomized clinical trials [24].(E) Risk of bias assessed by the JBI Critical Appraisal Tools for use in non-randomized clinical trials [24].
(A) Notes: ✓: Yes; --: No; U: Unclear; Quality items JBc1: Were the two groups similar and recruited from the same population?JBc2: Were the exposures measured similarly to assign people to both the exposed and unexposed groups?JBc3: Was the exposure measured in a valid and reliable way?JBc4: Were confounding factors identified?JBc5: Were strategies to deal with confounding factors stated?JBc6: Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?JBc7: Were the outcomes measured in a valid and reliable way?JBc8: Was the follow-up time reported and sufficient to be long enough for outcomes to occur?JBc9: Was follow-up complete and, if not, were the reasons for loss of follow-up described and explored?JBc10: Were strategies to address incomplete follow-up utilized?JBc11: Was appropriate statistical analysis used? (B) Notes: ✓: Yes; --: No; U: Unclear; Quality items JBcc1: Were the groups comparable other than the presence of disease in cases or the absence of disease in controls?JBcc2: Were cases and controls matched appropriately?JBcc3: Were the same criteria used for the identification of cases and controls?JBcc4: Was exposure measured in a standard, valid, and reliable way?JBcc5: Was exposure measured in the same way for cases and controls?JBcc6: Were confounding factors identified?JBcc7: Were strategies to deal with confounding factors stated?JBcc8: Were outcomes assessed in a standard, valid, and reliable way for cases and controls?JBcc9: Was the exposure period of interest long enough to be meaningful?JBcc10: Was appropriate statistical analysis used? (C) Notes: ✓: Yes; --: No; U: Unclear; Quality items JBcs1: Were there clear criteria for inclusion in the case series?JBcs2: Was the condition measured in a standard, reliable way for all participants included in the case series?JBcs3: Were valid methods used for the identification of the condition for all participants included in the case series?JBcs4: Did the case series have consecutive inclusion of participants?JBcs5: Did the case series have complete inclusion of participants?JBcs6: Was there clear reporting of the demographics of the participants in the study?JBcs7: Was there clear reporting of the clinical information of the participants?JBcs8: Were the outcomes or follow-up results of cases clearly reported?JBcs9: Was there clear reporting of the presenting site(s)/clinic(s)' demographic information?JBcs10: Was appropriate statistical analysis used? (D) Notes: ✓: Yes; --: No; U: Unclear; Quality items JBrct1: Was true randomization used for the assignment of participants to treatment groups?JBrct2: Was allocation to treatment groups concealed?JBrct3: Were treatment groups similar at the baseline?JBrct4: Were participants blind to treatment assignment?JBrct5: Were those delivering treatment blind to treatment assignment?JBrct6: Were outcomes assessors blind to treatment assignment?JBrct7: Were treatment groups treated identically other than the intervention of interest?JBrct8: Was follow-up complete and, if not, were differences between groups in terms of their follow-up adequately described and analyzed?JBrct9: Were participants analyzed in the groups to which they were randomized?JBrct10: Were outcomes measured in the same way for treatment groups?JBrct11: Were outcomes measured in a reliable way?JBrct12: Was appropriate statistical analysis used?JBrct13: Was the trial design appropriate, and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?(E) Notes: ✓: Yes; --: No; U: Unclear; Quality items JBnrct1: Is it clear in the study what is the 'cause' and what is the 'effect' (i.e., there is no confusion about which variable comes first)?JBnrct2: Were the participants included in any comparisons similar?JBnrct3: Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?JBnrct4: Was there a control group?JBnrct5: Were there multiple measurements of the outcome both pre and post the intervention/exposure?JBnrct6: Was follow-up complete and, if not, were differences between groups in terms of their follow-up adequately described and analyzed?JBnrct7: Were the outcomes of participants included in any comparisons measured in the same way?JBnrct8: Were outcomes measured in a reliable way?JBnrct9: Was appropriate statistical analysis used?

Quantitative Synthesis
After analyzing the 26 studies included in the meta-analysis, a total of 1473 patients who underwent CRS followed by HIPEC based on cisplatin, as defined above, were available for analysis.

Primary Endpoint: Incidence of Acute and Chronic Renal Impairment
The obtained results reflect an overall acute kidney injury (AKI, Figure 2A) incidence of 18.6% (95% CI: 13.6-25%).The observed high heterogeneity (I 2 = 82) is reflected in a wide range of true effects, producing an expanded predictive interval of 3-59%.(Figure 2B).This suggests that, by eliminating potential sources of error and bias through mathematical modeling, the incidence of AKI following cisplatin-based HIPEC would fall within the range of 3% to 59%.The I-squared (I 2 ) statistic reflects that 82% of the variance in the observed effects reflects variance in true effects rather than sampling error.

Quantitative Synthesis
After analyzing the 26 studies included in the meta-analysis, a total of 1473 patients who underwent CRS followed by HIPEC based on cisplatin, as defined above, were available for analysis.

Primary Endpoint: Incidence of Acute and Chronic Renal Impairment
The obtained results reflect an overall acute kidney injury (AKI, Figure 2A) incidence of 18.6% (95% CI: 13.6-25%).The observed high heterogeneity (I 2 = 82) is reflected in a wide range of true effects, producing an expanded predictive interval of 3-59%.(Figure 2B).This suggests that, by eliminating potential sources of error and bias through mathematical modeling, the incidence of AKI following cisplatin-based HIPEC would fall within the range of 3% to 59%.The I-squared (I 2 ) statistic reflects that 82% of the variance in the observed effects reflects variance in true effects rather than sampling error.
(A) (B) Another primary endpoint of this meta-analysis is the estimation of the global incidence of chronic kidney disease (CKD) following the intervention (Figure 3A).The results reveal a CKD rate of 7% (95% CI: 3-15.3%).Similarly to the AKI rate, the observed heterogeneity is high (I 2 = 75.89%).When calculating the range of true effects (Figure 3B), the CKD incidence would fall between 1-53%.Another primary endpoint of this meta-analysis is the estimation of the global incidence of chronic kidney disease (CKD) following the intervention (Figure 3A).The results reveal a CKD rate of 7% (95% CI: 3-15.3%).Similarly to the AKI rate, the observed heterogeneity is high (I 2 = 75.89%).When calculating the range of true effects (Figure 3B), the CKD incidence would fall between 1-53%.Given the high heterogeneity and the wide renal impairment range, the incidence rate has been disaggregated based on variables considered of interest for its possible impact on the observed effect.These variables (Table 1) are HIPEC regimen, cisplatin dose, HIPEC duration, etiology of PSM, incidence of acute renal injury with or without nephroprotection (single-arm or double-arm comparative studies), pre-existing chronic renal disease, and scale of renal impairment used.To carry out this analysis, some variables have been categorized.The breakdown analysis based on the previously mentioned variables is shown in Table 4.Among them, two yield statically significant results: the scale used to measure AKI and previous chronic kidney disease.Given the high heterogeneity and the wide renal impairment range, the incidence rate has been disaggregated based on variables considered of interest for its possible impact on the observed effect.These variables (Table 1) are HIPEC regimen, cisplatin dose, HIPEC duration, etiology of PSM, incidence of acute renal injury with or without nephroprotection (single-arm or double-arm comparative studies), pre-existing chronic renal disease, and scale of renal impairment used.To carry out this analysis, some variables have been categorized.The breakdown analysis based on the previously mentioned variables is shown in Table 4.Among them, two yield statically significant results: the scale used to measure AKI and previous chronic kidney disease.Regarding the use of renal insufficiency scales, the overall results (Table 4) obtained show that there are significant differences between the AKI incidences among the scales employed for assessing renal failure.This is additionally depicted in the forest plot shown in Figure 4. Regarding the use of renal insufficiency scales, the overall results (Table 4) obtained show that there are significant differences between the AKI incidences among the scales employed for assessing renal failure.This is additionally depicted in the forest plot shown in Figure 4.When conducting a variable effects analysis, it is observed that the presence of CKD is a protective factor against (Figure 5) the occurrence of acute renal failure following CRS and cisplatin-based HIPEC.Previous chronic kidney disease, regardless of its origin, may influence the use of cisplatin as the drug of choice for HIPEC.Some strategies employed to prevent AKI in patients with CKD include dose reduction.Alonso et al. [7] and Chen et al. [58] reduced the cisplatin dose by 25% in this subgroup of patients, although they did not specify in their analysis the number of patients with previous renal pathology included.When conducting a variable effects analysis, it is observed that the presence of CKD is a protective factor against (Figure 5) the occurrence of acute renal failure following CRS and cisplatin-based HIPEC.Previous chronic kidney disease, regardless of its origin, may influence the use of cisplatin as the drug of choice for HIPEC.Some strategies employed to prevent AKI in patients with CKD include dose reduction.Alonso et al. [7] and Chen et al. [58] reduced the cisplatin dose by 25% in this subgroup of patients, although they did not specify in their analysis the number of patients with previous renal pathology included.A third variable with significant impact on the incidence of renal impairment is the use of nephroprotection, regardless of whether it is ST or amifostine (Figure 6).The overall results of the use or non-use of nephroprotectors yield non-significant data.However, if we exclusively analyze studies in which a comparative design is employed, with one arm using a renal function preservation strategy and the other without it, the results differ (Figure 7).We obtain a relative risk of AKI of 7% (95% CI: 2-29%, p = 0.0003), favoring the use of nephroprotection.All included studies with a comparative group have a low risk of bias, but their designs vary: Laplace 2020 is an observational cohort study, Glennon 2021 is a case-control study, Senguttuvan 2023 is a non-randomized clinical trial, and Lim 2022 is a randomized clinical trial.A third variable with significant impact on the incidence of renal impairment is the use of nephroprotection, regardless of whether it is ST or amifostine (Figure 6).The overall results of the use or non-use of nephroprotectors yield non-significant data.However, if we exclusively analyze studies in which a comparative design is employed, with one arm using a renal function preservation strategy and the other without it, the results differ (Figure 7).We obtain a relative risk of AKI of 7% (95% CI: 2-29%, p = 0.0003), favoring the use of nephroprotection.All included studies with a comparative group have a low risk of bias, but their designs vary: Laplace 2020 is an observational cohort study, Glennon 2021 is a case-control study, Senguttuvan 2023 is a non-randomized clinical trial, and Lim 2022 is a randomized clinical trial.The remaining variables investigated do not exhibit a directly significant relationship with the incidence of AKI following cisplatin-based HIPEC administration, as shown in Table 4. Related figures are available in Supplementary Materials.

Discussion
To our knowledge, this is the first reported systematic review and meta-analysis on nephrotoxicity after complete CRS followed by cisplatin-based HIPEC.Our main goal was to determine the incidence of renal impairment (acute and chronic) associated with this treatment so that it can serve as a reference for future studies on this topic and for practice The remaining variables investigated do not exhibit a directly significant relationship with the incidence of AKI following cisplatin-based HIPEC administration, as shown in Table 4. Related figures are available in Supplementary Materials.

Discussion
To our knowledge, this is the first reported systematic review and meta-analysis on nephrotoxicity after complete CRS followed by cisplatin-based HIPEC.Our main goal was to determine the incidence of renal impairment (acute and chronic) associated with this treatment so that it can serve as a reference for future studies on this topic and for practice improvement or benchmarking.Additionally, we analyzed several variables that could influence the observed rates of acute and chronic renal impairment.
The unprecedented reported survival benefit by van Driel et al. in the OVIHIPEC-1 randomized clinical trial [8,10] is giving way to an increasing implementation of HIPEC with cisplatin in interval cytoreductive surgery for FIGO stage III epithelial ovarian cancer.The report of the CHIPOR trial by Classe et al. [9] (only available in abstract format at the time of writing this article), likewise showing significant survival benefits for peritoneal recurrence following induction systemic chemotherapy in this disease, adds to this phenomenon.This underscores the importance of studying short-and long-term renal toxicity following cisplatin-based HIPEC, its most concerning adverse effect.Interestingly, the dose of cisplatin employed differeed between both studies (100 mg/m 2 in OVHIPEC-1 and 75 mg/m 2 in CHIPOR) and neither trial specifically reported the incidence of renal impairment.For this reason, they are not included in this meta-analysis.PSOGI recently published a consensus on HIPEC regimens [140], recommending the use of the OVHIPEC-1 protocol (100 mg/m 2 fractionated in three doses together with intravenous ST) for cisplatin-based HIPEC in epithelial ovarian cancer.Several clinical trials are underway using HIPEC with different chemotherapeutic drugs to prevent or treat PSMs from various origins, including OVHIPEC-2, which explores the use of cisplatin-based HIPEC in epithelial ovarian cancer in the upfront setting.
Reports specifically on renal impairment following cisplatin-based HIPEC are relatively scarce compared with the broad body of literature on HIPEC and are highly heterogeneous.Since awareness of this adverse effect is needed, a clear idea of its magnitude is warranted.Our meta-analysis shows an incidence of 18.7% in AKI and 7% in CKD.The observed broad range in true effects makes interpretation difficult; it becomes challenging to make a clinical decision regarding a procedure associated with such a wide-ranging serious consequence.While AKI is oftentimes manageable and transitory, a 7% incidence of chronic kidney damage following a curative-intent procedure needs to be brought to the drawing board when indicating cisplatin-based HIPEC.
Therefore, nephroprotection should be considered when using cisplatin-based HIPEC.Van Driel et al. [8] used as part of their HIPEC protocol an intravenous infusion of ST aimed at preventing renal impairment.However, CHIPOR did not use nephroprotection.ST is indicated in the treatment of cyanide poisoning.The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved (September 2022 and March 2023, respectively) the intravenous infusion of ST to reduce hearing loss caused by cisplatin for non-metastatic solid tumors in pediatric patients.By extrapolation, off-label use of ST for renal protection is certainly an option, the same way it is used to treat calciphylaxis.Several other strategies have been reported to prevent cisplatin-based HIPEC-induced renal injury.These include the use of other intravenous nephroprotective agents (i.e., amifostine [123], cilastatin [110], forced diuresis and/or aggressive pre-hydration [141]).It is of utmost importance to keep in mind that many of the patients undergoing cisplatin-based HIPEC are likely to require additional systemic chemotherapy, making long-term organ functional preservation crucial.
Laplace et al. [6] published a prospective cohort compared with a retrospective cohort study with 66 patients diagnosed with PSMs of various origins that reflects the nephroprotective capability of ST after cisplatin-based HIPEC.The present systematic review and meta-analysis included studies using ST and amifostine, not showing differences in their capacity to prevent renal impairment.However, renal impairment was not their primary endpoint, and the assessment and categorization of renal damage was not homogeneous or standardized.In our study, the employment of nephroprotection only emerged as a significant variable impacting the incidence of renal failure when we specifically considered the studies that have two comparative arms, one using renal protection and a second arm without it.In this instance, the result differed from the overall findings, which showed no difference with the use of nephroprotection.
The most plausible explanation is that these studies were specifically designed to assess the incidence of renal failure as their primary endpoint, as an important detail that can exert a significant impact on their outcomes.All these studies include ST as nephroprotective agent and were published after the release of the initial report of van Driel et al.'s [8] study in 2018.The etiology of PSM in these studies, although varied, is mainly ovarian cancer [6,[119][120][121].Regarding the doses of cisplatin used, they range from 50 mg/m 2 to 100 mg/m 2 , and the duration of HIPEC varies between 60 and 90 min.The rate of acute renal failure is expressed using CTCAE (Sengutuvan et al. [120] and Lim et al. [119]), while Laplace et al. [6].use the WHO scale, and Glennon et al. [121] use KDIGO.
The renal impairment scale used to report cisplatin-based HIPEC nephrotoxicity was identified as one of the statistically significant variables impacting renal impairment incidence.To explain these findings, we searched the literature for a comparison among the different scales employed in the reports included in our meta-analysis.Although not established for CRS and HIPEC patients, it has been made for cardiac surgery patients [142], stating that RIFLE was superior to KDIGO and AKIN in terms of prognostic value for predicting mortality after isolated coronary artery bypass surgery.Additionally, Erdost et al. [143] compared these same three classifications for patients undergoing liver transplantation, another major abdominal surgery.Similarly to our findings, the results showed that AKI incidence varied depending on the scale used, and the perioperative risk factors for AKI changes with the scale as well.
These diverse renal impairment scales or classifications employed in the articles we reviewed establish different cut-off serum creatinine and/or urine output values or the need for renal replacement therapy, dialysis, in order to transition from one category to the next.They also differ in the consideration of both acute and chronic renal insufficiency.For example, when evaluating AKI using the Clavien-Dindo scale, distinguishing between grades 1 or 2 is challenging because it does not classify AKI until dialysis is required; the only difference between grade 1 and 2 is the pharmacological medical management.Exploring deeper into this comparison, AKIN 1 and 2 are analogous to CTCAE 2; meanwhile, AKIN 3 corresponds to CTCAE 3 and 4. The RIFLE scale uses cut-off points to establish Risk, Injury, and Failure stages, aligning with AKIN's.Loss and end-stage corresponds to CKD.
Descriptive and graphical comparisons between all scales are available in Table 5 and Figure 8, respectively.The heterogeneity in the reported data derived from this diversity makes a direct comparison of the studies considered in the present meta-analysis difficult.Descriptive and graphical comparisons between all scales are available in Table 5 and Figure 8, respectively.The heterogeneity in the reported data derived from this diversity makes a direct comparison of the studies considered in the present meta-analysis difficult.Standardization in the reporting of adverse effects within the field of surgical oncology is necessary.The use of the CTCAE scale was proposed by Younan et al. [144] as a result of an expert international consensus led by the PSOGI.However, it is true that the traditional use of the Clavien-Dindo classification in surgical services remains a practice difficult to change.
Finally, numerous clinical trials exclude patients diagnosed with any chronic organ dysfunction such as chronic kidney disease.Our study rendered an intriguing finding in that the presence of previous CKD acted as a protective factor for AKI following cisplatinbased HIPEC, with an incidence of AKI in previous CKD patients statistically significantly lower than in the non-previous CKD patient group.Several reasons might explain this finding, including the use of a cisplatin dose reduction or a more intensive monitoring of postoperative renal function in these patient groups.It is imperative to establish whether these patients could benefit from HIPEC with a presurgical organ preservation strategy.Multidisciplinary tumor conferences play a crucial role in these scenarios, where all care providers from each involved medical field must contribute, ensuring that the maximum possible number of patients can benefit from the best available treatment options.

Strengths and Limitations
This study is the first meta-analysis and systematic review that establishes the incidence of renal impairment, acute and chronic, after cisplatin-based HIPEC for patients with PSMs.It should serve as a reference for practice improvement and future reports on this topic.The methodology adhered strictly to PRISMA recommendations.
While the findings are promising and state the need for future research, it is essential to acknowledge certain limitations.Primarily, most of the included studies include retrospective cohorts and very few are non-randomized clinical trials.Additionally, the design of the studies that met the inclusion criteria were quite diverse: sixteen cohort studies (Table 3A), two case-control studies (Table 3B), one case series (Table 3C), one randomized clinical trial (Table 3D), and seven non-randomized clinical trials.However, despite the different designs, no significant differences were found when analyzing the incidence of renal impairment based on the study design used.However, although potential biases may exist, impacting consistency, the overall risk of bias of the included studies, as evaluated by JBI Critical Appraisal Tools assessment, was low.
Additionally, the high heterogeneity observed in this research complicates result interpretation.Factors like sample size, study design, classification of renal impairment, or studies not specifically designed to evaluate adverse events as the primary endpoint may influence results.These limitations emphasize the importance of improved adverse events reporting using standardized criteria and better-designed clinical trials.

Figure 2 .
Figure 2. (A) One-arm forest plot of acute kidney injury (AKI) incidence after the use of HIPEC in carcinomatosis patients.(B) AKI incidence true effects distribution (predictive interval).

Figure 2 .
Figure 2. (A) One-arm forest plot of acute kidney injury (AKI) incidence after the use of HIPEC in carcinomatosis patients.(B) AKI incidence true effects distribution (predictive interval).

JFigure 3 .
Figure 3. (A) Forest plot of chronic kidney disease (CKD) incidence after the use of HIPEC in PSM patients.(B) CKD incidence true effects distribution (predictive interval).

Figure 3 .
Figure 3. (A) Forest plot of chronic kidney disease (CKD) incidence after the use of HIPEC in PSM patients.(B) CKD incidence true effects distribution (predictive interval).

Figure 4 .
Figure 4. Forest plot of AKI incidence depending on the scale used.Figure 4. Forest plot of AKI incidence depending on the scale used.

Figure 4 .
Figure 4. Forest plot of AKI incidence depending on the scale used.Figure 4. Forest plot of AKI incidence depending on the scale used.

Figure 5 .
Figure 5. Forest plot of post cisplatin-based HIPEC AKI incidence in patients with previous CKD.

Figure 5 .
Figure 5. Forest plot of post cisplatin-based HIPEC AKI incidence in patients with previous CKD.

Figure 6 .
Figure 6.Forest plot of overall AKI incidence with or without nephroprotection (one-arm studies).

Figure 6 .
Figure 6.Forest plot of overall AKI incidence with or without nephroprotection (one-arm studies).

Figure 6 .
Figure 6.Forest plot of overall AKI incidence with or without nephroprotection (one-arm studies).

Figure 7 .
Figure 7. Incidence of AKI in 2-arm studies comparing the use versus non-use of nephroprotectors.

Figure 7 .
Figure 7. Incidence of AKI in 2-arm studies comparing the use versus non-use of nephroprotectors.
deviation from the normal postoperative course without the need for pharmacological treatment, or surgical, endoscopic, and radiological interventions Allowed therapeutic regimens are drugs including antiemetics, antipyretics, analgesics, and diuretics and electrolytes, and physiotherapy.This grade also includes wound infections opened at the bedside -Grade II Requiring pharmacological treatment with drugs other than such allowed for grade I complications.Blood transfusions and total parenteral nutrition are also complication (including central nervous system complications) requiring IC/ICU management • IVa: Single-organ dysfunction (including dialysis) • IVb: Multiorgan dysfunction -Risk, Injury, and Failure stages, aligning with AKIN's.Loss and end-stage corresponds to CKD.

Table 3 .
[26]Risk of bias assessed by the Joanna Briggs Institute (JBI) Critical Appraisal Tools for use in cohort studies[26].(B)Risk of bias assessed by the JBI Critical Appraisal Tools for use in casecontrol studies[26].(C) Risk of bias assessed by the JBI Critical Appraisal Tools for use in case series studies

Table 4 .
Main overall results and subgroup analysis of possible variables involved in AKI incidence.

Table 4 .
Main overall results and subgroup analysis of possible variables involved in AKI incidence.